Improvement in pulsed drug therapy

ABSTRACT

A dosage form comprising (1) an immediately available dose of a beneficial drug followed by a timed delayed dose of drug, or (2) a timed delayed dose of drug.

CROSS REFERENCE TO CO-PENDING APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.07/312,845 filed Feb. 21, 1989, now U.S. Pat. No. 4,986,987 issued Jan.22, 1991 which application Ser. No. 07/312,845, is a division of U.S.patent application Ser. No. 06/861,188, filed May 9, 1986, now U.S. Pat.No. 4,842,867, issued Jun. 27, 1989.

This invention pertains to a novel dosage form useful for the pulseddelivery of a beneficial drug. The dosage form, after an interval oftime, can deliver a single pulse or dose of drug, or the dosage form candeliver an initial pulse or dose of drug followed by a delayed pulse ordose of drug.

BACKGROUND OF THE INVENTION

Many beneficial drugs are administered at a definite time for theirbeneficial effects. For example, sleeping aids that help in fallingasleep are usually taken before bed and then, if needed, at a latertime, say four or five hours later. Then too, the symptomatic relief ofanxiety and tension, and the relief from pain and inflammation, usuallyrequires an initial pulse or first dose supplemented at a later intervalby another pulse or second dose. The pulsatile delivery of drugs havinga short half-life, that is drugs that lose one-half of their therapeuticactivity because the drug is metabolized or excreted, require pulsedadministration at recurring intervals. Also, it is often desirable toadminister a drug in a form that makes the drug available at a latertime for a pulsed delivery of a drug. The need for pulsed deliveryarises during a circadian or chronological cycle, for drugs with apronounced first post effect and for drugs which on continuous low levelmay lead to tolerance.

Prior to this invention, drugs with short half-lives were oftenadministered to a recipient once-or-twice in separate dosage formsduring a given time span, for example one-or-two doses to obtain thebenefit of the drugs pharmacokinetic activity. This type of repeateddosing is accompanied with shortcomings. For example, when a drug isadministered at bed time the presently available prior art dosage formsrequires repeated dosing the recipient and interrupting the sleep forthe next dose. Then too, a recipient on a therapeutic program oftenforgets to take the next dose, and this lack of compliance leads to adrug-free interval during which interval the recipient does not get thebenefit of the next needed dose.

It is immediately apparent in the light of the above presentation that apressing need exists for a dosage form that can delay the delivery of adrug and then deliver a pulsed dose of drug. It is apparent also that apressing need exists for a dosage form that can immediately deliver apulsed dose of drug followed by a drug-free interval and then deliver apulsed dose of drug. It will be appreciated by those versed in thedispensing art, that if a novel and unique dosage form is made availablefor executing a therapeutic program comprising pulsed and delayed drugdelivery patterns, such a dosage form would have a practical applicationand it would also represent a valuable contribution to the medical andveterinary arts.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a novel and useful dosage form thatrepresents an unexpected improvement in the dispensing art andsubstantially overcomes the disadvantages known to the prior art.

Another object of the present invention is to provide a dosage form thatcan deliver a pulsed dose of a beneficial drug.

Another object of the present invention is to provide a dosage form thatcan delay the delivery of the drug from the dosage form, and thendeliver a pulsed dose of the drug.

Another object of the present invention is to provide a novel dosageform comprising means for delivering an initial pulsed dose of drug,means for maintaining a drug-free interval, and means for delivering alater pulsed dose of drug at a later time.

Another object of the present invention is to provide a novel dosageform that overcomes the limited functionality of conventional dosagetablets, and which novel dosage form can preform a drug programcomprising delivering a drug at a pulsed rate and for a pulsed durationas needed to achieve a desired therapeutic program.

Another object of the invention is to provide a dosage form comprisingtwo doses of drug in a single dosage form that can be used for twice aday dosing of the drug.

Another object of the present invention is to provide a novel dosageform manufactured in the form of a drug delivery device comprising meansfor delivering a pulsed dose of drug, means for providing a drug-freeinterval, and means for then providing a recurring pulsed dose.

Another object of the invention is to provide a dosage form comprisingtwo doses in a single dosage form.

Another object of the present invention is to provide a dosage formcomprising an exterior member for providing an immediate pulsed dose ofdrug, and an internal member for providing a delayed pulsed dose ofdrug.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing art from the followingspecification, taken in conjunction with the drawing figures and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

FIG. 1 is a general view of a dosage form provided by the invention,which dosage form is designed and shaped for oral administration, fordelayed, or pulsed patterns of drug delivery to the gastrointestinaltract;

FIG. 2 is a view of an osmotic dosage form provided by the inventioncomprising an exterior dosage amount of drug for the initial pulseddelivery of the drug to the gastrointestinal tract;

FIG. 3 is an opened view of a dosage form provided by the invention,which dosage form delays the pulsed delivery of a dose amount of drug tothe gastrointestinal tract;

FIG. 4 is an opened view of a dosage form provided by the inventionwhich dosage form provides an initial pulsed dose of drug followed by adrug-free interval and then another pulsed dose of drug; and,

FIG. 5 is an opened view of another embodiment of the invention forproviding a first dose of drug and at a later time a second dose ofdrug.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures arean example of the dosage form provided by the invention, and whichexamples are not to be construed as limiting, one example of the dosageform is illustrated in FIG. 1 and designated by the numeral 20. In FIG.1, dosage form 20 comprises a body member 21 comprising a wall 22 thatsurrounds and forms an internal compartment not seen in FIG. 1. Dosageform 20 further comprises at least one exit means 23 for connecting theinterior of dosage form 20 with the exterior environment of use.

FIG. 2 illustrates dosage form 20 of FIG. 1 comprising body 21, wall 22,exit means 23 and exterior lamina 24. Exterior lamina 24 comprises adosage unit amount of drug for an initial pulsed dose of drug to theenvironment of use, the gastrointestinal tract of a warm-blooded animal.The initial pulse is the first dose of drug. Exterior lamina 24comprises from about 0.1 to 99.9 weight percent (wt. %) of a drug, andfrom 99.9 to 0.1 wt. % of a pharmaceutically acceptable carrier for thedrug, with the total wt. % of all lamina 24 forming members equal to100%. In a more preferred embodiment the initial pulse dose is from 10to 80 wt % and from 90 to 20 wt % carrier. The carrier is a means forcoating the drug onto the exterior surface of the wall, and the carriercomprising lamina 24 onto the exterior surface of wall 22. In the fluidenvironment of use, the carrier releases the drug thereby providing theinitial or first pulsed dose of the drug to the environment of use. Thecarrier releases the initial pulsed dose in from greater than zero timeup to 1 hour, and in a presently preferred pulsed dose time of fromseveral minutes up to 30 minutes. Typical carrier means include ahydrophilic polymer, that are in a presently preferred embodiment amember selected form the group consisting of hydroxymethyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose and hydroxypropyl ethylcellulose

FIG. 3 is a view of dosage form 20 seen in opened view with wall 22sectioned at 25 for illustrating the internal structure of dosage form20. In FIG. 3, osmotic dosage form 20 comprises body 21, wall 22 thatsurrounds and defines an interior compartment 26 and at least one exitmeans 23. Wall 22 of dosage form 20 comprises at least in part, ortotally, a composition that is permeable to the passage of an exteriorfluid present in the environment of use, and it is substantiallyimpermeable to the passage of drug and other ingredients present incompartment 26. Wall 22 is comprised of a polymeric composition that isinert and maintains its physical and chemical integrity during the lifetime of dosage form 20. The phrase, "physical and chemical integrity"denotes wall 22 does not lose its structure and it does not changeduring the dispensing life of dosage form 20. Typical materials forforming wall 22 comprise selectively semipermeable polymers known to theart as osmosis and reverse osmosis polymers. These polymericcompositions comprise a cellulose ester, cellulose ether, celluloseester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, and cellulosetriacetate. In a presently preferred embodiment wall 22 is a compositioncomprising cellulose acetate having an acetyl content of 32%, celluloseacetate having an acetyl content of 39.8%, hydroxypropyl methylcelluloseand polyethylene glycol. In one example wall 22 is a compositioncomprising from 15 to 45 wt. % cellulose acetate having an acetylcontent of 32%; 15 to 45 wt. % cellulose acetate having an acetylcontent of 39.8%; from 5 to 35 wt. % of hydroxypropyl methylcellulose;and from 5 to 35 wt. % polyethylene glycol 3350.

Internal compartment 26 in one preferred embodiment houses a first layercomprising a beneficial drug formulation 27, identified by dots, and ahydrogel carrier 28, identified by dashes, for drug formulation 27.Hydrogel carrier means 28 comprises a hydrophilic composition that isnoncross-linked, or lightly cross-linked, and it possesses the abilityto form a dispensable, pulsed drug formulation by homogeneously blendingwith drug formulation 27. In operation, hydrogel carrier means 28absorbs and/or imbibes fluid and expands to form a dispensable pulsedformulation that is released from dosage form 20 transporting drugformulation 27 therewith. The pulsed dose has generally a pulsedduration of 10 minutes to 200 minutes, and more preferably 20 minutes to40 minutes. Generally, the dosage unit amount of drug blended with thehydrogel carrier means is about 1 to 80 wt. %.

Internal compartment 26 houses a second layer 29 comprising a hydrogelmember and in a presently preferred embodiment an osmagent blended withthe hydrogel member. The hydrogel comprising second layer 29 exhibitsfluid absorbing and/or fluid imbibing properties. The hydrogel comprisedof a hydrophilic polymer interacts with water and aqueous biologicalfluids and swells or expands to an equilibrium state. The hydrogelexhibits the ability to swell in aqueous fluid and retain a significantportion of the absorbed or imbibed fluid within the polymer structure.In operation, the first layer and the second layer cooperate to deliverthe drug formulation from dosage form 20. In operation, the second layer29 absorbs fluid, expands and exerts pressure against the first layer.Simultaneously, the first layer absorbs fluid and forms a dispensableformulation. By the combined operation of the first and second layers,with the second layer expanding against the first layer and urging itfrom the compartment, and with the first layer forming a dispensableformulation, the drug formulation is delivered from the dosage form.

The hydrogel composition comprising carrier means 28 and second layer 29swell or expand to a very high degree, usually exhibiting from theirnonhydrated state a 2 to 50 fold increase in volume. The hydrogelcomprising carrier means 28, for the purpose of this invention, is adifferent hydrogel than the hydrogel comprising second layer 29. Thehydrogel comprising carrier means 28 and the hydrogel comprising secondlayer 29, in operation, cooperate to deliver the pulsed dose of drugfrom the dosage form. Representative hydrophilic hydrogels consists of amember selected from the group consisting of poly(hydroxyalkylmethacrylate) having a molecular weight of 20,000 to 5,000,000;poly(vinylpyrrolidone) having a molecular weight of about 10,000 to360,000; poly(vinyl alcohol) having a low acetate content and lightlycross-linked with glyoxal, formaldehyde, glutaraldehyde and having adegree of polymerization rpm 200 to 30,000; poly(ethylene oxide) havinga molecular weight form 10,000 to 5,000,000; acidic carboxy polymersknown as carboxypolymethylene and carboxyvinyl polymers, a polymerconsisting of acrylic acid lightly cross-linked with pollyallyl-sucroseand sold under the trademark Carbopol®, acidic carboxy polymer having amolecular weight of 200,000 to 6,000,000, including sodium acidiccarboxyvinyl hydrogel and potassium acidic carboxyvinyl hydrogel;Cyanamer® polyacrylamide; and the like. The representative polymers areknown to the art in Handbook of Common Polymers, by Scott and Roff,published by the Chemical Company, Cleveland, Ohio; ACS SymposiumSeries, No. 31, by Ratner and Hoffman, pp. 1 to 36, 1976, published bythe American Chemical Society; and in Recent Advances In Drug DeliverySystems, by Schacht, pp. 259 to 278, published by Plenum Press, N.Y.

Second layer 29 can comprise optionally an osmagent blended with thehydrophilic polymer. The osmagent is present to aid in imbibing exteriorfluid through wall 22 and into second layer 29. The dual action of theosmagent imbibing fluid and the hydrogel imbibing fluid results in anincrease in the expansion of layer 29 thereby assuring substantiallycomplete delivery of drug formulation 27 from dosage form 20. Osmagentsare known also as osmotically effective solutes and osmoticallyeffective compounds. The osmagents are soluble in fluid that enters thedosage form, and they exhibit an osmotic pressure gradient acrosssemipermeable wall 22 against an exterior fluid. Osmotically effectiveosmagents useful for the present purpose include magnesium sulfate,magnesium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium sulfate, sodium carbonate, lithium sulfate, sodiumsulfate, and the like. The osmagent is usually present as a particle,powder, granule, or the like. The amount of active osmagenthomogeneously or heterogeneously blended with the hydrophilic hydrogelin the second layer is usually form 0.01% to 45%, or higher. The osmoticpressure in atmospheres, ATM, of the osmagent suitable for the inventionwill be greater than zero ATM, generally from zero ATM up to 500 ATM, orhigher. The osmotic pressure of an osmagent is measured in acommercially available osmometer that measures the vapor pressuredifference between pure water and the solution to be analyzed, andaccording to standard thermodynamic principles the vapor pressure ratiois converted into an osmotic pressure difference. The osmometer used forthe present measurements is identified as Model 1001-A Vapor PressureOsmometer, manufactured by Knauer and distributed by Utopia InstrumentCo., Joliet, Ill.

Dosage form 20 of FIG. 3 comprises internal delayed coat 30 thatsurrounds the first layer and the second layer. Delayed coat 30 is adrug-free coat. Delayed coat 30 provides an interval of time duringwhich dosage form 20 postpones the delivery of drug formulation 27.Delayed coat 30 in its initial dry state is about 0.1 mm to 10 mm thick,and in a more presently preferred range delayed coat 30 is about 4 to 7mm thick. Delayed coat 30 is a means for delaying the delivery of drugformulation for about 1 hour to 12 hours, preferably 2 hours to 9 hours,and in a presently more preferred embodiment it provides a drug-freeinterval of 3 hours to 6 hours. Delayed coat 30 comprises initially adry hydrophilic polymer such as a member selected from the groupconsisting of hydroxypropyl methylcellulose, hydroxypropylcellulose,methylcellulose, carboxymethylcellulose, hydroxyethylcellulose,hydroxymethylcellulose, and the like. Delayed coat 30 can comprise alsoa member selected from the group consisting of poly(oxyethylene),poly(vinyl pyrrolidone), carboxyvinyl polymer, and the like.

FIG. 4 illustrates another dosage form 20 provided by the invention.Dosage form 20 makes available the pulsed delivery of drug followed by adrug-free interval, and then a final pulsed dose of drug. This dosageform also exemplifies a single dosage form comprising two distinct andindependent doses of drug. Dosage form 20 of FIG. 4 comprises exteriorpulsed drug coat 24 that surrounds in at least a part exterior wall 22of body 21 of dosage form 20. Dosage form 20 also comprises an exitpassageway 23 that communicates the exterior of dosage form 20 withinternal compartment 26. Internal compartment 26 comprises a first layerthat comprises drug formulation 27 and carrier means 28, and a secondlayer comprising a hydrogel composition 29. An inner positioned delayed,drug-free coat 30 is located between the inside surface of wall 20 andit surrounds both inner contacting layers in compartment 26. Dosage form20, is sized, shaped and designed for oral admittance into thegastrointestinal tract of a warm-blooded animal including a human.Dosage form 20 is manufactured as an osmotic device and it provides apulsed-delayed-pulsed drug pattern or first dose delay second dose inthe manner described for the above drawing figures

FIG. 5 illustrates another dosage form 20 provided by the invention.Dosage form 20 of FIG. 5 comprises body 21, wall 22 comprising at leastin part a semipermeable composition, which wall is sectioned at 25, exitmeans 23, exterior lamina 24 comprising a first dosage amount of drug,interior drug release delaying lamina 30, internal compartment 26housing a second dosage amount of orally administrable drug 27 and,optionally, a hydrogel 28.

The expression "exit means" as used herein comprises means and methodssuitable for releasing the pulsed dose from compartment 26. Theexpression includes at least one passageway or orifice that passesthrough wall 22 for communicating with compartment 26. The expression"at least one passageway" includes aperture, orifice bore, pore, porouselement through which drug can migrate, a hollow fiber, capillary tubeand the like. The expression includes also a material that erodes or isleached from wall 22 in the fluid environment of use to produce at leastone passageway in the dosage form. Representative materials suitable forforming at least one passageway, or a multiplicity of passagewaysinclude an erodible poly(glycolic) or poly(lactic) acid member in thewall, a gelatinous filament, leachable materials such as fluid removablepore forming polysaccharides, salts or oxides, and the like. Apassageway or a plurality of passageways can be formed by leaching amaterial such as sorbitol from the wall to produce a controlled releasepassageway. The passageway can have any shape, such as round,triangular, elliptical, and the like. The device can be constructed withone or more passageways in spaced apart relation on more than a singlesurface of a dosage form. Passageways and equipment for formingpassageways are disclosed in U.S. Pat. Nos. 3,916,899; 4,063,064 and4,088,864. Passageways of controlled dimensions formed by leaching aredisclosed in U.S. Pat. No. 4,200,098.

The expression "drug formulation", as used herein, denotes anybeneficial agent, compound, or composition of matter, that can bedelivered by the dosage form in pulsed doses or first and second dosesto produce a beneficial, therapeutic results. The drugs for the presentpurpose include any physiologically or pharmacologically activesubstance that produces a local or a systemic effect in animals. Theterm animals includes warm-blooded mammals, humans, primates, household,sport, farm and zoo animals. The term "physiologically" as used hereindenotes the administration of a drug to produce normal levels andfunctions. The term "pharmacologically" denotes variations in responsesto various amounts of drug administered to the host. Stedman's MedicalDictionary, 1966, published by Williams and Wilkins, Baltimore, Md. Theactive drugs that can be delivered include inorganic and organic drugswithout limitations, drugs that can act on the central nervous system,depressants, hypnotics, sedatives, psychic energizers, tranquilizers,anticonvulsants, muscle relaxants, antiparkinson agents,anti-inflammatories, local anesthetics, muscle contractants,antimicrobials, antimalarials, hormonal agents, contraceptives,diuretics, sympathomimeters, antiparasitics, neoplastics, hypoglycemics,ophthalmics, electrolytes, diagnostics, cardiovascular drugs, and thelike. The beneficial drugs are known to the art in PharmaceuticalSciences, by Remington, 14 Ed., 1979 published by Mack Publishing Co.,Easton, Pa.; The Drug, The Nurse, The Patient, Including Current DrugHandbook, 1974-76 by Falconer et al., published by Sounder Company,Philadelphia, Pa.; and Physician's Desk Reference, 40th Ed., 1986,published by Medical Economics Co., Oradell, N.J.

The wall of the dosage form, and the exterior pulsed release lamina canbe formed in one technique using the air suspension procedure. Thisprocedure consists in suspending and tumbling delayed, coated bilayersin a current of air and a wall forming, or outer pulsed laminacomposition, until in either operation the wall or the pulsed lamina isapplied to the delayed coated bilayers. The air suspension procedure iswell-suited for independently forming the wall of the pulsed lamina. Theair suspension procedure is described in U.S. Pat. No. 2,799,241; in J.Am. Pharm. Assoc., Vol. 48, pp. 451 to 459, 1959; and, ibid, Vol.49, pp.82 to 84, 1960. The osmotic dosage-pulsed-delayed systems can also becoated with the wall forming composition, or the lamina pulsedcomposition with a Wurster® air suspension coater, using for examplemethylene dichloride - methanol cosolvent. The Aeromatic® air suspensioncoater can be used also employing a cosolvent. Other wall and laminatingtechniques such as pan coating can be used for providing the dosageform. In the pan coating system the wall forming, or the pulsed laminaforming, compositions are deposited by successive spraying of thecomposition on the delayed coated bilayers accompanied by tumbling in arotating pan. A pan coater is used to produce a thicker wall or lamina.A larger volume of methanol can be used in a cosolvent to produce athinner wall or lamina. Finally, the wall or lamina coated compartmentsare dried in a forced an oven at 50° C. for a week, or in a temperatureand humidity controlled over for 24 hours at 50° C. and 50 relativehumidity, to free the dosage form of solvent. Generally, the wall formedby these techniques have a thickness of 2 to 20 mils with a presentlypreferred thickness of 4 to 10 mils. The exterior pulsed dose laminagenerally will have a thickness of 0.5 to 15 mils, usually 0.5 to 7.5mils.

Exemplary solvents suitable for manufacturing the wall or the laminainclude inert inorganic and organic solvents that do not adversely harmthe wall, the lamina and the final dosage system. The solvents broadlyinclude a member selected form the group consisting of an alcohol,ketone, ester, ether, aliphatic hydrocarbon, halogenated solvents,cycloaliphatic solvents, aromatic, heterocyclic, aqueous solvents, andmixtures thereof.

The dosage form of the invention is manufactured by standard techniques.For example, in one manufacture the beneficial drug and otheringredients comprising the first layer facing the exit means are blendedand pressed into a solid layer. The layer possesses dimensions thatcorrespond to the internal dimensions of the area the layer is to occupyin the dosage form and it also possesses dimensions corresponding to thesecond layer for forming a contacting arrangement therewith. The drugand other ingredients can be blended also with a solvent and mixed intoa solid or semisolid form by conventional methods such as ballmilling,calendering, stirring or rollmilling and then pressed into a preselectedshape. Next, a layer of hydrogel is placed in contact with the layer ofdrug in a like manner. The layering of the drug formulation and thehydrogel layer can be fabricated by conventional two-layer presstechniques. The two contacted layers are first coated with a delayeddrug-free overcoat and then with the outer wall. The drug-free delayedcomposition can be applied by press coating, molding, spraying, dipping,and air suspension procedures. The air suspension and air tumblingprocedure comprises in suspending and tumbling the pressed, contactingfirst and second layers in a current of air containing thedelayed-forming composition until the first and second layers aresurrounded by the delayed composition.

In another manufacture, the dosage form is manufactured by the wetgranulation technique. In the wet granulation technique the drug and theingredients comprising the first layer are blended using an organiccosolvent, such as isopropyl alcohol-methylene dichloride 80/20 v/v(volume/volume) as the granulation fluid. The ingredients forming thefirst layer are individually passed through a 40 mesh screen and thenthoroughly blended in a mixer. Next, other ingredients comprising thefirst layer are dissolved in a portion of the granulation fluid, thecosolvent described above. Then, the latter prepared wet blend is slowlyadded to the drug blend with continual mixing in the blender. Thegranulating fluid is added until a wet blend is produced, which wet massblend is then forced through a 20 mesh screen onto oven trays. The blendis dried for 18 to 24 hours at 35° C. in a forced air oven. The driedgranules are then sized with a 20 mesh screen. Next, magnesium stearateis added to the dry screened granule blend, and this blend passedthrough an 80 mesh screen. The granulation is then put into milling jarsand mixed on a jar mill for 5 to 10 minutes. The composition is pressedinto a layer, for example in a 3-station Manesty® layer press. The speedof the press is set at 30 rpm and the maximum load set at 2 tons. Thefirst layer is pressed against the composition forming the second layerand the bilayer tablets are fed to the Kiliam® dry Coata press andsurrounded with the drug-free coat followed by the exterior wall solventcoating.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for examplepoly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders are then dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is added to the granulator. The granules are thenpressed in the manner described above.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those versed in the art in the light of the presentdisclosure, the drawing figures and the accompanying claims.

EXAMPLE 1

A dispensing device is manufactured for delivery a beneficial drug asfollows: a first layer and a second layer are compressed in contactingarrangement in a three layer press under a 11/2 ton pressure head. Thefirst layer is made from granules of a homogeneous master blendcomprising 570 g of polyethylene oxide having a molecular weight of200,000; 400 g of midazolam; and 30 g of hydroxypropylmethyl cellulose.The ingredients are dry blended, then wetted with 350 ml of anhydrousethanol, followed by drying in an oven for 17 to 20 hrs at 30° C. Thedry granules then are passed through a 30 mesh screen. The second layeris formed from a composition comprising 650 g of polyethylene oxidehaving a molecular weight of 5,000,000; 290 g of sodium chloride; 50 gof hydroxypropylmethyl cellulose: and 10 g of ferric oxide. Thematerials comprising the second layer are blended and then wetted with950 ml of anhydrous ethanol. The wet granules are dried at 30° C. for 15to 20 hrs in a forced air oven, and then passed through a 20 mesh sieve.

The granules for the first layer forming composition are transferred tothe number 1 hopper, and the granules for the second layer formingcomposition are added to the number 2 hopper of the press. The first andsecond layers are pressed together with the first layer weighing 12.5 mgand the second layer weighing 50 0 mg, with a diameter of 4.76 mm.

A delay layer coating is applied with a Kilian® dry Coata press. Thepressed together layers are transferred to the Coata press hopper, and adelay composition comprising hydroxypropyl cellulose is dry coatedaround the first and second layers. The delay coated first and secondlayers have a diameter of 7 mm.

Next, the delayed coated layers are transferred to an Aeromatic® airsuspension coater. The systems are surrounded with a semipermeablewall-forming composition for applying a 4 mg wall per system. The wallforming composition comprises 30 wt. % cellulose acetate having anacetyl content of 39.8%; 30 wt. % cellulose acetate having an acetylcontent of 32%; 20 wt. % polyethylene glycol 400; and 20 wt. %hydroxypropylmethyl cellulose. The wall forming ingredients aredissolved in a cosolvent comprising methylene chloride: methanol (85:15wt. %) to obtain 5% solids.

Finally, a first and a second passageway are drilled through the wallfor connecting the exterior of the dosage form with the interior of thedosage form. A passageway is drilled on two distant surfaces of thedosage form. The dosage forms are dried in a forced air oven at 50° C.for 40 hrs to remove all residual solvent. The dosage forms are sizedand shaped for oral admittance into the gastrointestinal tract of ahuman.

EXAMPLE 2

The procedure of Example 1 is repeated in this example with allmanufacturing steps as previously set forth, except that in this examplethe wall comprising the semipermeable composition is coated with apulsed coat of drug. The pulsed coat is applied to the exterior surfaceof the wall from a composition comprising 50 wt. % midazolam, 25 wt. %hydroxypropyl cellulose and 25 wt. % tartaric acid, dissolved indistilled water to obtain 15 wt. % solids. The pulsed coat applied toeach dosage form contains 10 mg of midazolam.

Next, a pair of passageways were drilled through the outer-most pulsedcoat and the wall for connecting the exterior of the wall for connectingthe exterior of the dosage form with its compartment. The dosage form isdried as described previously.

The dosage form prepared according to the example releases the 10 mg ofmidazolam in about 10 minutes. The first pulsed release is followed by a31/2 hour drug-free period. The second dose of midazolam is delivered inabout 1/2 hour for 80% of the drug with substantially all of the drugdelivered in about 1 to 11/2 hours.

EXAMPLE 3

The procedures of Examples 1 and 2 are repeated in this example. In thisexample, the first layer weighed 18.75 mg, the second layer weighed 70mg, the internal delay layer weighed 110 mg, the wall weighed 4.5 mg andthe outermost coat contained 15 mg of midazolam. The dosage formreleased 15 mg of midazolam in a first 15 minute pulsed period, anddelivered 7.5 mg of midazolam after a 3.5 hour delay.

EXAMPLE 4

The procedure of Example 1 is followed for manufacturing a dosage formcomprising two 6.5 mil (0.17 mm) passageways on two opposite surfaces ofthe dosage form. The dosage form delivered the internally housedmidazolam after a 3.5 hour delay with 80% delivered in about 1/2 hour.

EXAMPLE 5

The procedures of Examples 1 and 4 are followed that the interior houseddelayed composition comprises hydroxypropylmethyl cellulose 47.5 wt %;hydroxypropyl cellulose 50 wt. % and polyvinyl pyrrolidone 2.5 wt. %.

EXAMPLES 6 AND 7

The above procedure is repeated with the manufacturing conditions as setforth, with one example comprising an internal delay layer weighing 80mg that release the drug after 2.8 hours; and another internal delaycoat weighing 120 mg that permits the dosage form to deliver the drugafter a 4.6 hour delay period of time.

EXAMPLE 8

A dosage form for use as a nighttime sleep-aid comprising an exteriorpulsed dose of diphenhydramine hydrochloride, and an internal pulseddose of diphenhydramine is made as follows: a first layer comprising 50mg of diphenhydramine hydrochloride, polyethylene oxide having amolecular weight of 120,000 and hydroxypropylmethyl cellulose, ispressed in contacting position to a second layer comprising polyethyleneoxide having a molecular weight of 5,000,000 and sodium chloride. Thetwo layers are first surrounded with a delay coat comprisinghydroxypropyl cellulose, and then with a wall comprising cellulosetriacetate having an acetyl content of 43.5% and cellulose acetatehaving an acetyl content of 32%. The wall is coated on its outer surfacewith an instant pulsed dose coat comprising 25 mg of diphenhydraminehydrochloride, hydroxypropyl cellulose and citric acid. The dosage formis made with a pair of spaced-apart passageways. The dosage form isadministered one at bed time for the relief of sleeplessness. The dosageform delivers the outer pulsed dose and after a 3 to 31/2 hour drug-freeperiod, delivers the internal dose. The dosage form is blister packedfor ease of administration.

EXAMPLE 9

The procedure of Example 8 is repeated with the condition as describedpreviously except that in this example the dosage form internallycontained in the first layer 15 mg of doxylamine succinate, and 10 mg ofdoxylamine succinate in the exterior coat. The dosage form isadministered about 30 minutes before retiring as nighttime sleep aid.

EXAMPLE 10

A dosage form for the relief of menstrual pain and more particularlymenstrual and premenstrual pain and discomfort is made in accordancewith the above described procedures. The dosage form comprises aninternal first layer comprising 200 mg of acetaminophen, 34 mg ofpamabrom (2-amino-2-methyl-1-propanol-8-bromo-theophyllinate), and 17 mgof pyrilamine maleate, polyethylene oxide having a molecular weight of120,000 and hydroxypropylmethyl cellulose, a second layer comprisingCyanamer® A-370 a hydrogel polyacrylamide of about 200,000 molecularweight, and sucrose; and an outermost exterior pulsed coat comprising100 mg of acetaminophen, 16 mg of pamabrom and 8 mg of pyrilaminemaleate. The dosage form after administration delivers an instant pulsedosage amount followed by repeated dosage amount of the beneficial drugs3 to 4 hours later. The dosage form provided by the invention compriseswithin a single dosage form a first dose and a repeat dose substantialequivalent to multiples of twice, thrice a day or the like.

EXAMPLE 11

A dosage form comprising dimenhydrinate indicated for the prevention andthe treatment of nausea, vomiting or vertigo of motion sickness isprepared according to the procedure of Example 10. The dosage formcomprises 50 mg of dimenhydrinate in the first layer and 50 mg ofdimenhydrinate in the outer pulsed dose. The dosage form is indicatedfor preventing motion sickness by taking the dosage form 1/2 to 1 hourbefore starting the activity, thereby providing a first instant dosefollowed by a repeat dose 3 to 4 hours later from the same dosage form.

EXAMPLE 12

A dosage form comprising two independently administrable doses with theadministration of a first dose followed by the administration of asecond dose at a later time from the same, single dosage form is madeaccording to the above procedures. In this example, the dosage formcomprises an internal 5 mg dose of methamphetamine hydrochloride, ananoretic for use in obesity, in the first layer, and 5 mg of the sameanoretic in the outermost first dose coat. The dosage form can beadministered once a day taken one-half hour before a meal, usuallybefore breakfast or lunch.

EXAMPLE 13

A dosage form for use as a nightime cough relief up to 12 full hours ismanufactured as described in Example 8. The dosage form of this examplecomprises two doses in a single dosage form indicated for convenientb.i.d. dosing that helps quiet coughs during the night. The exteriorfirst dose of the dosage form comprises 15 mg of dextromethorphan HBr,and the later delivered second does comprises 15 mg of dextromethorphanHBr. The dosage form is administered orally on retiring forsubstantially avoiding interrupted rest.

EXAMPLE 14

A single dosage form comprising two distinct and timed separate dosesuseful for administering the antihistamine chlorprophenpyridaminemaleate is manufactured as described above. The dosage form comprises animmediately timed released external first dose comprising 6 mg ofchlorprophenpyridamine and a later timed released second dose comprising6 mg of chlorprophenpyridamine for producing approximately ten hourssymptomatic antihistamine relief to the recipient.

EXAMPLE 15

A dosage form for use as a sleep-aid is provided by following the abovemanufacture procedures. The dosage form of this example comprises aninternal compartment 26, drug formulation 27 comprising 60 mg ofdiphenhydramine hydrochloride and 340 mg of polyethylene oxide having amolecular weight of 10,000. The drug formulation 27 is surrounded with adelay lamina comprising hydroxypropyl cellulose and then with a laminacomprising cellulose acetate having an acetyl content of 32%. Anexterior lamina for providing an instant pulse dosage of 20 mg ofdiphenhydramine hydrochloride, hydroxypropyl cellulose and adipic acid.The dosage form comprises a first and a second passageway, and when inoperation it provides an instant first dose followed by delayed seconddose delivered 3 to 31/2 hours later.

EXAMPLE 16

The above procedures are followed in this example for manufacturing adosage form comprising a first pulse of 0.15 mg of the sedativetriazolam and a later time delayed second pulse of 0.1 mg of triazolam.

In summary, it will be readily appreciated that the present inventioncontributes to the art an unobvious dosage form manufactured as a drugdelivery device possessing wide and practical application. While theinvention has been described and pointed out in detail and withreference to operative embodiments thereof, it will be understood thatthose skilled in the art will appreciate that various changes,modifications, substitutions and omissions can be made without departingform the spirit of the invention. It is intended, therefore, that theinvention embrace those equivalents within the scope of the claims whichfollow.

What is claimed is:
 1. An improvement in a chronological dosage form fordelivering a beneficial drug to a drug recipient, wherein the dosageform comprises:(a) a wall comprising at least in part a compositionpermeable to the passage of fluid, which wall surrounds and forms; (b) acompartment; (c) a drug formulation in the compartment; (d) at least oneexit means in the wall for delivering the drug from the dosage form, andwherein the improvement comprises: (e) means in the compartment fordelaying the delivery of drug from the dosage form, which meanscomprises a drug-free 0.1 mm to 10 mm thick lamina that delays thedelivery of drug for up to 12 hours and surrounds the drug formulationfor providing drug at a delayed time for therapy int he recipient.